A transplant to replace damaged tissues with healthy ones from either living or decreased individuals of the same species is called an allograft. Tissues and cells from another individual are usually recognized as foreign by the mammalian immune system. This stimulates a response of the host defenses to reject the foreign tissue. The immune system can occasionally recognize very small differences in molecular structure and develop an alloimmune response. Some cell types are very similar among individuals such as blood cells. It is possible to administer blood products such red blood cells, and plasma without an immune response if the blood type is compatible. Virtually all mammalian cells, except red blood cells, express major histocompatibility molecules on their cell surface. These molecules are a critical mechanism by which the immune system can distinguish self from foreign cells.
Organ transplantation is the definitive therapy for many forms of end-stage disease of the kidney, liver, heart, lung, pancreas and intestine. Transplantation of specialized cells such as islets of Langerhans and nerve cells are becoming more common, as well as complex tissue transplantation such as a limb or face. However, the long-term success of these procedures is limited by the immune response. Unless the donor is an identical twin, most recipients must take immunosuppressive medications. Current immunosuppressive therapies are not capable of preventing rejection in all cases, and have multiple significant side effects. These drugs may lead to life threatening infection, cardiovascular disease, diabetes, and cancer.
A number of methods are currently used to monitor the function of transplanted organs and tissue: serum creatinine for kidney, serum transaminases for liver, ejection fraction for heart, oxygen saturation for lung, and serum glucose for pancreas transplant. Unfortunately, these tests have poor sensitivity or specificity for rejection. In many cases the definitive test for organ rejection is an invasive and expensive biopsy.
The histologic patterns of rejection are different for each organ and distinct patterns of tissue injury can be identified for “cellular” versus “humoral” rejection. This distinction is important since the best treatment for “cellular” rejection may be administration of immunosuppressive medications targeted to prevent further proliferation of T lymphocytes, while “humoral” rejection is treated by medications that suppress B lymphocytes and clear the plasma of the antibodies which recognize the graft as foreign. In general, a mild cellular rejection can frequently be reversed and may not cause long-term injury. Humoral rejection is more difficult to reverse and has a higher risk of leading to poor graft function. In many cases of transplant rejection there are components of both a cellular and humoral immune response combined. The gold standard for classification of transplant rejection is allograft biopsy.
Despite significant improvements in one-year allograft function with current immunosuppressive strategies, there has been less progress in the long term maintenance of graft function. It is hypothesized that both immunologic and non-immunologic factors such as drug toxicity or hypertension contribute to this disease. Chronic transplant dysfunction is a phenomenon in solid organ transplants with a gradual deterioration of function accompanied by characteristic histological features on graft biopsy. In kidney transplantation, this is known as chronic rejection, chronic allograft nephropathy (CAN), or interstitial fibrosis with tubular atrophy (IFTA). In heart transplantation there is accelerated atherosclerosis and in liver transplantation the bile ducts atrophy. Chronic transplant injury is characterized by fibrosis of the internal blood vessels of the transplant and may be related to sub-clinical AMR. Detecting this problem at an early stage is difficult even with protocol biopsy.
Current diagnostic methods of renal allograft rejection are neither sensitive nor specific. Needle biopsies are invasive and associated with patient morbidity. Thus, it is desirable to develop noninvasive tests to predict and diagnose rejection.